The present invention relates to a compound known as aloe-emodin (AE) as an active agent for the preparation of pharmaceutical compositions for the treatment of neuroectodermal tumors.
It is known that the therapeutic strategies used at present in the treatment of neoplastic pathologies essentially aim at eliminating all malignant cells both on the primary and metastatic sites. To this purpose different therapeutic modalities can be used, from surgery to radiotherapy for tumors which are localized, to chemotherapy for local or distant diseases, to endocrine therapy for hormone-dependent tumors, to immunotherapy up to thermotherapy. All these therapeutic modalities can be used singularly or can also be combined one with the other, according to the type of neoplastic cells and to the stage of the pathology, in order to obtain an effective therapy of eradication of neoplasia.
Chemotherapy is certainly one of the most common therapeutic approaches, both alone and combined with the aforesaid therapeutic modalities. An ideal chemotherapy agent should be selective for the tumoral cells without inducing any relevant adverse effects on normal cells or toxic effects of systemic type; nevertheless, in spite of the long and complex research aiming at finding anti-cancer agent of this kind, up to now no compound, used singularly and combined with other agents, has proved to have a satisfactory therapeutic index, i.e. the effectiveness ratio on the tumoral cells versus absence of cytotoxic effects on non-malignant cells. Several anti-tumor agents are knows and in use, and there are highly different mechanisms causing their cytotoxicity towards tumoral cells. The first agents to be used were alkylating drugs, such as nitrogen mustard, followed by anti-metabolic drugs, folate antagonists such as methotrexate, or purine antagonists such as 6-mercaptopurine, or pirimidine antagonists such as 5-fluorouracil, substances of vegetal origin blocking cell mitosis such as vincristine and vinblastine, and podophyllotoxins, antibiotics such as mitomycin, adriamycin and bleomycin, nitrosoureas, platinum coordination compounds and more recently the so-called biologic response modifiers such as xcex1-interferon and an enzyme such as asparaginase. All these drugs, alone or in combination, are broadly used for several tumoral pathologies from tumors localized in specific organs to disseminated tumors. In the case of neuroectodermal tumors, such as for instance neuroblastoma, primitive peripheral neuroectodermic tumor (pPNET), Ewing""s sarcoma, melanoma, microcytoma etc., the chemotherapy agents normally used, though not specific, can be for instance vincristine and vinblastine, platinum coordination compounds and others suitable to this purpose.
Despite the recognized effectiveness of many among these compounds, none of them has nevertheless proved to have the aforesaid ideal profile, and in several cases a certain resistance, also multiple, of tumoral cells towards these agents can even be observed, though toxic effects on other cells do not disappear.
Therefore, with the aim of developing novel anticancer drugs characterized by selective targeting and low toxicity for dividing normal host tissues, the inventors have focused their attention on natural compounds, which have been traditionally used for centuries to treat a wide and various range of highly heterogeneous pathologies and which are characterized in that they have no relevant toxic effect, studying in particular their cytotoxicity towards tumoral cells of human origin, which are not usually used in screenings to verify the potential anti-tumoral effect of known and new compounds.
After these researches the inventors have now found that a natural substance of vegetal origin, aloe-emodin, surprisingly has a powerful cytotoxic activity, both in vitro and in vivo, against cells of neuroectodermal tumors, without showing a similar cytotoxic activity for dividing normal host tissues.
Aim of the present invention is therefore the use of aloe-emodin for the preparation of pharmaceutical compositions which can be used in the treatment of neuroectodermal tumors.
Aloe-emodin can act as chemotherapy agent inducing a selective cytotoxicity towards those cells through an apoptotic mechanism.